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Quantifying the contribution of gluconeogenesis to glucose production in fasted human subjects using stable isotopes

Published online by Cambridge University Press:  12 June 2007

Bernard R. Landau
Bernard R. Landau*
Affiliation:
Departments of Medicine, Biochemistry, and Nutrition, Case Western Reserve University School of Medicine, Cleveland, OH 44106–4951, USA
*
Corresponding Author: Professor B. R. Landau, fax +1 216 368 4937, email epc2@po.cwru.edu
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Abstract

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The contribution of gluconeogenesis to glucose production is estimated from the enrichment of the H bound to C-5 of glucose relative to either that bound to C-2 of glucose or the enrichment in body water on ingesting 2H2O in the fasted state. Contributions of all gluconeogenic substrates are included in the estimate and the limitation of an uncertain precursor enrichment removed. The half-life of 2H2O in body water precludes a repeat study for many weeks. Glycogen cycling could result in underestimation, but there is evidence that glycogen cycling does not occur in liver in the fasted state. Gluconeogenesis has been estimated by mass-isotopomer-distribution analyses, usually by administering 13C-labelled glycerol. Underestimates emphasize the major limitation of the method, i.e. the need to assume a single enrichment of the precursor pool. Estimates of gluconeogenesis from isotopomer distribution in arterial-blood glucose and lactate on infusing [U-13C6] glucose are unreliable, as a proportion of the glucose is formed from glycerol and from amino acids not converted to glucose via pyruvate. Loss of label in the Krebs cycle and relying on enrichment of arterial-blood lactate as a measure of hepatic pyruvate further add to the uncertainty. Estimates of the rate of gluconeogenesis by NMR are obtained by subtraction of the rate of glycogenolysis determined by NMR from the rate of glucose production. Estimates are then the mean rate for the period over which glycogen contents are measured. Technical considerations can limit the accuracy of analyses and result in overestimates.

Keywords

2H-labelled waterGluconeogenesisStable isotopesNMRMass-isotopomer analysis
Type
Meeting Report
Information
Proceedings of the Nutrition Society , Volume 58 , Issue 4 , November 1999 , pp. 963 - 972
Copyright
The Nutrition Society

References

Ameer, B, Divoll, M, Abernethy, DR, Greenblatt, DJ & Shargel, L (1983) Absolute and relative bioavailability of oral acetaminophen preparations. Journal of Pharmaceutical Sciences 72, 955–958.CrossRefGoogle ScholarPubMed
Bjorkman, O, Felig, P & Wahren, J (1980) The contrasting responses of splanchnic and renal glucose output to gluconeogenic substrates and to hypoglucagonemia in 60-h-fasted humans. Diabetes 29, 610–616.CrossRefGoogle ScholarPubMed
Bondy, PK, James, SF & Farra, BW (1949) Studies of the role of the liver in human carbohydrate metabolism by the venous catheter technic. I. Normal subjects under fasting conditions and following the injection of glucose. Journal of Clinical Investigation 28, 238–244.CrossRefGoogle ScholarPubMed
Chandramouli, V, Ekberg, K, Schumann, WC, Kalhan, SC, Wahren, J & Landau, BR (1997) Quantifying gluconeogenesis during fasting. American Journal of Physiology 273, E1209–E1215.Google ScholarPubMed
Chandramouli, V, Ekberg, K, Schumann, WC, Wahren, J & Landau;, BR (1999) Origins of the hydrogen bound to carbon 1 of glucose in fasting: significance of gluconeogenesis quantitation. American Journal of Physiology 277, E717–E723.Google ScholarPubMed
Chen, X, Igbal, N & Boden, G (1999) The effects of free fatty acids on gluconeogenesis and glycogenolysis in normal subjects. Journal of Clinical Investigation 103, 365–372.CrossRefGoogle ScholarPubMed
Chiasson, JL, Liljenquist, JE, Lacy, WW, Jennings, AS & Cherrington, AD (1977) Gluconeogenesis: methodological approach in vivo. Federation Proceedings 36, 229–235.Google Scholar
Christiansen, M, Linfoot, P, Neese, R, Turner, S & Hellerstein, MK (1995) Gluconeogenesis in NIDDM. Effect of energy restriction. Diabetes 44, 553A.Google Scholar
Cori, CF (1931) Mammalian carbohydrate metabolism. Physiological Reviews 11, 143–275.CrossRefGoogle Scholar
Davidson, AM & Halestrap, AP (1988) Inorganic pyrophosphate is located primarily in the mitochondria of the hepatocyte and increases in parallel with the decrease in light-scattering induced by gluconeogenic hormones, butyrate and ionophore A23187. Biochemical Journal 254, 379–384.CrossRefGoogle ScholarPubMed
DeFronzo, R, Ferrannini, E, Hendler, R, Felig, P & Wahren, J (1983) Regulation of splanchnic and peripheral glucose uptake by insulin and hyperglycemia in man. Diabetes 32, 35–45.CrossRefGoogle ScholarPubMed
DeFronzo, RA, Gunnarsson, R, Bjorkman, O, Olsson, M & Wahren, J (1985) Effects of insulin on peripheral and splanchnic glucose metabolism in noninsulin-dependent (type II) diabetes mellitus. Journal of Clinical Investigation 76, 149–155.CrossRefGoogle ScholarPubMed
Dekker, E, Hellerstein, MK, Romijn, JA, Neese, RA, Peshu, N, Endert;, E, Marsh, K & Sauerwein, HP (1997a) Glucose homeostasis in children with falciparum malaria: precursor supply limits gluconeogenesis and glucose production. Journal of Clinical Endocrinology and Metabolism 82, 2514–2521.Google ScholarPubMed
Dekker, E, Romijn, JA, Ekberg, K, Wahren, J, Thien, HV, Ackermans, MT, Thuy, LTD, Chandramouli, V, Kager, PA, Landau, BR & Sauerwein, HP (1997b) Glucose production and gluconeogenesis in adults with uncomplicated falciparum malaria. American Journal of Physiology 272, E1059–E1064.Google ScholarPubMed
Des Rosiers, C, Landau, BR & Brunengraber, H (1990) Interpretation of isotopomer patterns in tracing glycogen synthesis and glucose recycling using (13C6) glucose. American Journal of Physiology 259, E757–E762.Google ScholarPubMed
Diraison, F, Large, V, Brunengraber, H & Beylot, M (1998) Non-invasive tracing of liver intermediary metabolism in normal subjects and in moderately hyperglycaemic NIDDM subjects. Evidence against increased gluconeogenesis and hepatic fatty acid oxidation in NIDDM. Diabetologia 41, 212–220.CrossRefGoogle ScholarPubMed
Diraison, F, Large, V, Maugeais, C, Krempf, M & Beylot, M (1999) Noninvasive tracing of human liver metabolism: comparison of phenylacetate and apoB-100 to sample glutamine. American Journal of Physiology 277, E529–E536.Google ScholarPubMed
Ekberg, K, Landau, BR, Wajngot, A, Chandramouli, V, Efendic, S, Brunengraber, H & Wahren, J (1999) Splanchnic and renal glucose production in the postabsorptive state in healthy humans. Diabetes 48, 292–298.CrossRefGoogle Scholar
Esenmo, E, Chandramouli, V, Schumann, WC, Kumaran, K, Wahren, J & Landau, BR (1992) Use of 14CO2 in estimating rates of hepatic gluconeogenesis. American Journal of Physiology 263, E36–E41.Google ScholarPubMed
Freedmann, B, Goodman EH., Jr & Weinhouse, S (1963) Liver glycogen synthesis in intact alloxan diabetic rats. Journal of Biological Chemistry 238, 2899–2905.CrossRefGoogle Scholar
Fried, R, Beckmann, N, Keller, U, Ninnis, R, Stalder, G & Seelig, J (1996) Early glycogenolysis and late glycogenesis in human liver after intravenous administration of galactose. American Journal of Physiology 270, G14–G19.Google ScholarPubMed
Gay, KJ, Schneiter, P, Schutz, Y, DiVetta, V, Jequier, E & Tappy, L (1994) A non-invasive assessment of hepatic glycogen kinetics and post absorptive-gluconeogenesis in man. Diabetologia 37, 517–523.CrossRefGoogle ScholarPubMed
Guynn, RW, Veloso, D, Randolph Lawson, JW & Veech, RL (1974) The concentration and control of cytoplasmic free inorganic pyrophosphate in rat liver in vivo. Biochemical Journal 140, 369–375.CrossRefGoogle ScholarPubMed
Hellerstein, MK, Greenblatt, DJ & Munro, HN (1986) Glycoconjugates as noninvasive probes of intrahepatic metabolism: pathways of glucose entry into compartmentalized hepatic UDP-glucose pools during glycogen accumulation. Proceedings of the National Academy of Sciences USA 83, 7044–7048.CrossRefGoogle ScholarPubMed
Hellerstein, M, Neese, R, Linfoot, P, Christiansen, M & Turner, S (1995) Contribution from gluconeogenesis measured by mass isotopomer analysis in normal humans. Diabetes 44, 153A.Google Scholar
Hellerstein, MK, Neese, RA, Linfoot, P, Christiansen, M, Turner, S & Letscher, A (1997) Hepatic gluconeogenic fluxes and glycogen turnover during fasting in humans. Journal of Clinical Investigation 100, 1305–1319.CrossRefGoogle ScholarPubMed
Hetenyi G., Jr, Perez, G & Vranic, M (1983) Turnover and precursor-product relationships of nonlipid metabolites. Physiological Reviews 68, 606–665.CrossRefGoogle Scholar
Hother-Nielsen, O & Beck-Nielsen, H (1990) On the determination of basal glucose production rate in patients with type 2 (non-insulin-dependent) diabetes mellitus using primed-continuous 3-3H-glucose infusion. Diabetologia 33, 603–610.CrossRefGoogle ScholarPubMed
Jeng, CY, Sheu, WH, Fuh, MM, Chen, YD & Reaven, GM (1994) Relationship between hepatic glucose production and fasting plasma glucose concentration in patients with NIDDM. Diabetes 43, 1440–1444.CrossRefGoogle ScholarPubMed
Kalderon, B, Korman, SH, Gutman, A & Lapidot, A (1989) Glucose recycling and production in glycogenosis type I and III: stable isotope technique study. American Journal of Physiology 257, E346–E353.Google ScholarPubMed
Kalhan, SC, Rossi, K, Gruca, L, Burkett, R & O'Brien, A (1997) Glucose turnover and gluconeogenesis in human pregnancy. Journal of Clinical Investigation 100, 1775–1781.CrossRefGoogle ScholarPubMed
Katz, J, Lee, WNP, Wals, PA & Bergner, EA (1989) Studies of glycogen synthesis and Krebs cycle by mass isotopomer analysis with [U-13C]glucose in rats. Journal of Biological Chemistry 264, 12994–13001.CrossRefGoogle ScholarPubMed
Katz, J & Tayek, JA (1998) Gluconeogenesis and Cori cycle in 12-, 20- and 40-h-fasted humans. American Journal of Physiology 275, E573–E574.Google ScholarPubMed
Katz, J, Wals, PA, Bergner, EA & Lee, WNP (1991a) Mass isotopomer studies of glycogen synthesis in vivo. In Regulation of Hepatic Function, Alfred Benzon Symposium no. 30, pp. 400–412 [Grunnet, N and Quistorff, B, editors]. Copenhagen: Munksgaard.Google Scholar
Katz, J, Wals, PA & Lee, WN (1991b) Determination of pathways of glycogen synthesis and the dilution of the three-carbon pool with (U-13C)glucose. Proceedings of the National Academy of Sciences USA 88, 2103–2107.CrossRefGoogle ScholarPubMed
Katz, J, Wals, PA & Rognstad, R (1978) Glucose phosphorylation, glucose-6-phosphatase, and recycling in rat hepatocytes. Journal of Biological Chemistry 253, 4530–4546.CrossRefGoogle ScholarPubMed
Landau, BR (1993) Measuring glucose and fructose-6-phosphate cycling in liver in vivo. Metabolism 42, 457–462.CrossRefGoogle ScholarPubMed
Landau, BR (1997) Stable isotope techniques for the study of gluconeogenesis in man. Hormone and Metabolic Research 29, 334–336.CrossRefGoogle Scholar
Landau, BR (1999) Limitations in the use of [U-13C]glucose to estimate gluconeogenesis. American Journal of Physiology 277, E408–E413.Google ScholarPubMed
Landau, BR, Chandramouli, V, Schumann, WC, Ekberg, K, Kumaran, K, Kalhan, SC & Wahren, J (1995a) Rates of Krebs cycle activity and contributions of gluconeogenesis to hepatic glucose production in fasting healthy subjects and IDDM patients. Diabetologia 38, 831–838.CrossRefGoogle ScholarPubMed
Landau, BR, Fernandez, CA, Previs, SF, Ekberg, K, Chandramouli, V, Wahren, J, Kalhan, SC & Brunengraber, H (1995b) A limitation in the use of mass isotopomer distributions to measure gluconeogenesis in fasting humans: Hepatic heterogeneity in glycerol metabolism. American Journal of Physiology 269, E18–E26.Google Scholar
Landau, BR, Wahren, J, Chandramouli, V, Schumann, WC, Ekberg, K & Kalhan, S (1995c) Use of 2H2O for estimating rates of gluconeogenesis. Application to the fasted state. Journal of Clinical Investigation 95, 172–178.CrossRefGoogle Scholar
Landau, BR, Wahren, J, Chandramouli, V, Schumann, WC, Ekberg, K & Kalhan, SC (1996) Contributions of gluconeogenesis to glucose production in the fasted state. Journal of Clinical Investigation 98, 378–385.CrossRefGoogle ScholarPubMed
Landau, BR, Wahren, J, Ekberg, K, Previs, SF, Yang, D & Brunengraber, H (1998) Limitation in gluconeogenesis and Cori cycling estimates from mass isotopomer distribution using (U-13C6)glucose. American Journal of Physiology 274, E954–E961.Google ScholarPubMed
Lee, WP, Bassilian, S, Bergner, EA, Wals, P & Katz, J (1994) Mass isotopomer study of gluconeogensis from 13C-labeled lactate in man. Clinical Research 42, 28A.Google Scholar
Lundquist, F, Tygstrup, N, Winkler, K & Jensen, KB (1965) Glycerol metabolism in the human liver: inhibition by ethanol. Science 150, 616–617.CrossRefGoogle ScholarPubMed
Magnusson, I, Chandramouli, V, Schumann, WC, Kumaran, K, Wahren, J & Landau, BR (1987) Quantitation of the pathways of hepatic glycogen formation on ingesting a glucose load. Journal of Clinical Investigation 80, 1748–1754.CrossRefGoogle ScholarPubMed
Magnusson, I, Chandramouli, V, Schumann, WC, Kumaran, K, Wahren, J & Landau, BR (1988) Pentose pathway in human liver. Proceedings of the National Academy of Sciences USA 85, 4682–4685.CrossRefGoogle ScholarPubMed
Magnusson, I, Rothman, DL, Jucker, B, Cline, GW, Shulman, RG & Shulman, GI (1994) Liver glycogen turnover in fed and fasted humans. American Journal of Physiology 266, E796–E803.Google ScholarPubMed
Magnusson, I, Rothman, DL, Katz, LD, Shulman, RG & Shulman, GI (1992) Increased rate of gluconeogenesis in type II diabetes mellitus. A 13C nuclear magnetic resonance study. Journal of Clinical Investigation 90, 1323–1327.CrossRefGoogle ScholarPubMed
Magnusson, I, Schumann, WC, Bartsch, GE, Chandramouli, V, Kumaran, K, Wahren, J & Landau, BR (1991) Noninvasive tracing of Krebs cycle metabolism in liver. Journal of Biological Chemistry 266, 6975–6984.CrossRefGoogle ScholarPubMed
Magnusson, I, Wennlund, A, Chandramouli, V, Schumann, WC, Kumaran, K, Wahren, J & Landau, BR (1990) Fructose-6-phosphate cycling and the pentose cycle in hyperthyroidism. Journal of Clinical Endocrinology and Metabolism 70, 461–466.CrossRefGoogle ScholarPubMed
Neese, RA, Schwarz, JM, Faiz, D, Turner, S, Letscher, A, Vu, D & Hellerstein, MK (1995) Gluconeogenesis and intrahepatic triose phosphate flux in response to fasting or substrate loads. Journal of Biological Chemistry 270, 14452–14466.CrossRefGoogle ScholarPubMed
Newsholme, E & Leech, A (1985) Biochemistry for the Medical Sciences, p. 586. New York: John Wiley & Sons.Google Scholar
Peroni, O, Large, V & Beylot, M (1995) Measuring gluconeogenesis with (2-13C)glycerol and mass isotopomer distribution analysis of glucose. American Journal of Physiology 269, E516–E523.Google Scholar
Petersen, KF, Krssak, M, Navarro, V, Chandramouli, V, Hundal, R, Schumann, WC, Landau, BR & Shulman, GI (1999) Contributions of net glycogenolysis and gluconeogenesis to glucose production in cirrhosis. American Journal of Physiology 276, E529–E535.Google ScholarPubMed
Petersen, KF, Laurent, D, Rothman, DL, Cline, GW & Shulman, GI (1998) Mechanism by which glucose and insulin inhibit net hepatic glycogenolysis in humans. Journal of Clinical Investigation 101, 1203–1209.CrossRefGoogle ScholarPubMed
Petersen, RF, Price, T, Cline, GW, Rothman, DL & Shulman, GI (1996) Contribution of net hepatic glycogeneolysis to glucose production during the early postprandial period. American Journal of Physiology 270, E186–E191.Google Scholar
Previs, SF, Cline, GW & Shalman, GI (1999) A critical evaluation of mass isotopomer distribution analysis of gluconeogenesis in vivo. American Journal of Physiology 277, E154–E160.Google ScholarPubMed
Previs, SF, Fernandez, CA, Yang, D, Soloviev, MV, David, F & Brunengraber, H (1995) Limitations of the mass isotopomer distribution analysis of glucose to study gluconeogenesis. Substrate cycling between glycerol and triose phosphates in liver. Journal of Biological Chemistry 270, 19806–19815.CrossRefGoogle ScholarPubMed
Previs, SF, Hallowell, PT, Neimanes, KD, David, F & Brunengraber, H (1998) Limitations of the mass isotopomer distributions analysis of glucose to study gluconeogenesis. Journal of Biological Chemistry 273, 16853–16859.CrossRefGoogle ScholarPubMed
Rognstad, R, Clark, DG & Katz, J (1974) Glucose synthesis in tritiated water. European Journal of Biochemistry 47, 383–388.CrossRefGoogle ScholarPubMed
Rothman, DL, Magnusson, I, Katz, LD, ShulmanRG, RG, & Shulman, GI (1991) Quantitation of hepatic glycogenolysis and gluconeogenesis in fasting humans with 13C NMR. Science 254, 573–576.CrossRefGoogle Scholar
Siler, SQ, Neese, RA, Christiansen, MP & Hellerstein, MK (1998) The inhibition of gluconeogenesis following alcohol in humans. American Journal of Physiology 275, E897–E907.Google ScholarPubMed
Stumvoll, M, Chintalapudi, U, Perriello, G, Welle, S, Gutierrez, O & Gerich, J (1995) Uptake and release of glucose by the human kidney. Postabsorptive rates and responses to epinephrine. Journal of Clinical Investigation 96, 2528–2533.CrossRefGoogle ScholarPubMed
Tayek, JA & Katz, J (1996) Glucose production, recycling, gluconeogenesis in normals and diabetics: a mass isotopomer [U-13C] glucose study. American Journal of Physiology 270, E709–E717.Google ScholarPubMed
Tayek, JA & Katz, J (1997) Glucose production, recycling, Cori cycle and gluconeogenesis in humans: relationship to serum cortisol. American Journal of Physiology 272, E476–E484.Google ScholarPubMed
Wahren, J, Efendic, S, Luft, R, Hagenfeldt, L, Bjorkman, O & Felig, P (1977) Influence of somatostatin on splanchnic glucose metabolism in postabsorptive and 60-hour fasted humans. Journal of Clinical Investigation 59, 299–307.CrossRefGoogle ScholarPubMed
Wajngot, A, Chandramouli, V, Schumann, WC, Ekberg, K, Efendio, S & Landau, BR (1999) Contribution of gluconeogenesis to glucose production in mild type 2 diabetics. Diabetologia 42 Suppl. 1 , (In the Press).Google Scholar
Wajngot, A, Chandramouli, V, Schumann, WC, Kumaran, K, Efendic, S & Landau, BR (1989) Testing of the assumptions made in estimating the extent of futile cycling. American Journal of Physiology 256, E668–E675.Google ScholarPubMed
Wi, JK, Kim, JK & Youn, JH (1996) Mechanisms of postabsorptive hyperglycemia in streptozotocin diabetic rats. American Journal of Physiology 270, E752–E758.Google ScholarPubMed
Wykes, LJ, Jahoor, F & Reeds, PJ (1998) Gluconeogenesis measured with (U-13C) glucose isotopomer analysis of apoB-100 amino acids in pigs. American Journal of Physiology 274, E365–E376.Google ScholarPubMed